Hypoxic ischemia (HI) injury to brain results in both oxidative and excitotoxic stresses that provoke numerous pathophysiological and discrete electrical functional changes. Our prior brain research has led to methods that can calibrate the magnitude an duration of injury by using electrical indicators of EEG and evoked potentials (EP). The overall goal of the present proposal is to evaluate cerebral electrical signaling to provide even more important information about the response of brain to delayed injury stresses as well as recovery. The central hypothesis is that mathematical and experimental evaluation of cerebral electrical signaling will provide novel mechanistic insights into the precise temporal profile of recovery from HI injury in terms of delayed injury, early recovery, and later recovery. Aim 1 will focus on delayed injury. Cortical neuroelectric signals will be quantitatively evaluated to determine recovery of low frequencies and coarse shape details in the EP signals and an irregular recovery of the dominant frequencies of EEG. Multi-unit recording in the dorsal thalamus and reticular thalamus will test their possible central role in initiating recovery via the thalamocortical circuit. Since delayed injury is marked by excess excitatory neurotransmitter activity, the role of glutamate release inhibition and glutamate transporter knockdown on modulating the degenerative changes will be assayed neurochemically. Aim 2 will examine early recovery. Cortical signals will be characterized for the return of high frequencies and fine details in EP signals as well as spindling and burst suppression in the EEG signals. Cellular studies will determine the post-HI response to somatosensory stimuli and spindle oscillations in the thalamic relay neurons co- incident with animal's recovery. Electrophysiological investigations of somatosensory pathway and molecular manipulation of receptor density and synaptic transmission during restoration of thalamocortical circuit function will define the mechanisms of early recovery. Aim 3 will explore the late recovery by evaluating the subject's survival and any neurological deficits after therapies initiated in the earlier phases. Restoration of EP and EEG signal features will be quantified by a combined linear and non-linear modeling scheme. Effects on extended recovery of cortical and thalamic electrical signals will be compared to two contrasting manipulations: inhibition of synaptic glutamate release versus glutamate transporter knockdown. Immunochemical analysis will identify structural modifications resulting in regenerative changes and good functional recovery in thalamocortical pathways and the somatosensory cortex. The innovative use of quantitative analysis of cortical and thalamic signals coupled with novel neurochemical validation of injury and recovery mechanisms should led to the discovery of basic electrophysiological mechanisms differentiating various phases of global HI injury. The long-term benefits should be improved diagnosis and novel therapeutic strategies targeted to each phase of recovery from HI injury.